Finding cancer before it starts

by Joyce Peterson / Photography by Stanton Short

Late November brought good news from a large coalition of U.S. researchers: a report that cancer deaths and overall cancer incidence in men and women had dropped for the first time.

But the authors of the report noted that certain cancers had actually increased in frequency, adding that "ongoing research is needed to improve our current methods of prevention, early detection and treatment."
Kevin Mills, Ph.D., is finding cancer before it even starts, right in the chromosomes. Now, that's early detection.

"The standard approach to understanding cancer has been to study tumors, in people and animals who are already sick, and work backwards to trace their formation," says Dr. Mills, an assistant professor at The Jackson Laboratory. "This approach has helped us find many clues to specific kinds of cancer.

"But for someone wondering what his or her own cancer risk is, it provides only a broad statistical probability. Each person's cancer is a unique disease. We're looking at normal chromosomes to understand how cancer begins in the first place."

Chromosomes are packets of DNA found inside the nucleus of every cell, in every plant and every animal. Today, a process called spectral karyotyping uses fluorescent dyes that bind to specific chromosomes. After computer processing, the image of each chromosome appears in a different color, making identification a snap. More important, the spectacular images clearly show where a genetic accident has occurred, as when a saffron band matching Chromosome 16 appears in otherwise aqua Chromosome 4.

Seeing your chromosomes

Translocations and other chromosomal rearrangements can happen during everyday cell division, and they don't always have health effects. But they can be the very first sign of cancer. Dr. Mills is studying the chromosomal rearrangements that occur in B-cell acute lymphoblastic leukemia (B-ALL), one of the most common childhood cancers. In B-ALL, too many immature white blood cells (B-cell lymphoblasts) populate the blood and bone marrow.

"What are the mechanisms and the cellular pathways and the processes that maintain a normal, stable genome?" Dr. Mills asks. "And how does the genome become destabilized? What are the patterns of instability, the patterns of rearrangements? And once we've deciphered the patterns of chromosomal instability, how does that translate into cancer?"

Dr. Mills and his Jackson colleagues have observed that double-strand breaks and subsequent chromosomal rearrangements lead to cancer in mouse models of B-ALL. "This raises the possibility of designing very early cancer screening methods, to detect these very early events in the chromosomes," he says.

Home of the gene detectives

If there's a world capital of scientists who are skilled at watching genes in action, The Jackson Laboratory may well be it. Its Microscopy Services group provides the spectral karyotyping images that Dr. Mills uses to find the colorful evidence of chromosomal translocations. The Laboratory is also home to the world's most powerful light microscopes: the nation's only 4Pi confocal laser scanning microscope and the even more awe-inspiring FPALM microscope developed by a Jackson team of optical physicists, which has achieved a tenfold increase of resolution over the 4Pi.

Assistant Professor Lindsay Shopland, Ph.D., works with the Laboratory's biophysics group in collaboration with colleagues at the University of Maine, the University of Heidelberg and the Maine Medical Center Research Institute.

Dr. Shopland, who works closely with Dr. Mills, is conducting her own research into the early events of cancers. "We're able to target the exact sites where DNA breaks lead directly to tumor formation," she says. One of these sites is a cancer-causing gene, or oncogene, known as myc(pronounced "mick"). Dr. Shopland and her colleagues have observed the DNA in myc replicating itself over and over in a long chain. "This chain breaks away and makes a long, amplified bit of chromosome on its own," she says, which is the first step in tumor formation. Post-break, the original chromosome then rearranges itself in its own telltale pattern.

Early cancer detection

Despite success in observing these and other early cancer mechanisms, Dr. Shopland isn't satisfied. "We don't know exactly why all this happens," she says. "It's one of the things we're trying to figure out."

But, Dr. Mills asserts, "Now we know the changes to look for in some cancers. And we're going to use that knowledge to design better clinical approaches to looking for the changes."

"Mice allow us to track cancer right from the very beginning, which is something we haven't been able to do in the clinical samples," Dr. Mills says. "We're working on designing a diagnostic method that looks at the human genes that correspond with the relevant mouse genes." He adds that his lab is already collaborating with a clinical researcher to explore new approaches to diagnosing B-ALL and other leukemias.

"We hope to develop diagnostic technology for use right in the clinic, to test a patient's DNA for the very specific profile we've identified." Fortunately, he notes, this diagnostic approach is simple and affordable, and "doesn't require every clinic to have a million-dollar microscope in its basement" like the 4Pi.